The aim of the proposed work is to use a combination of enzymatic, structural, biochemical, and biological approaches to study the structural/function relationship of quinone reductase 2 (QR2). The biological functions of QR2 are still virtually unknown, even though its close homolog, quinone reductase 1 (QR1), is well characterized. Our recent studies indicate that quinone reductase 2 (QR2) is the potential target of many natural polyphenols, including resveratrol analogs, flavonoids, chalconoids and some coumarin derivatives. QR2 is also active in the reduction of nitro groups of CB1954 and catechol quinones such as adrenochrome. QR2 knock down by RNAi method further demonstrated that resveratrol treated cells and QR2 knockdown cells exhibit similar properties: resistance to quinone toxicity, increased expression of anti-oxidant enzymes, and reduced proliferation rate. Based on those studies, we hypothesize that QR2 possesses very different functions from QR1 by virtual of its unique properties in substrate specificities, interacting protein partners, and inhibitors apart from QR1. We further hypothesize that QR2 is potentially a critical regulator, directly or indirectly, in the expression of antioxidant enzymes, such as catalase and glutathione reductases. Therefore, we propose to study the catalytic properties of QR2 with substrate specificity studies, especially the catalytic activity towards neurotoxic quinones and drug metabolites;inhibitor specificity studies;elucidation of QR2 structures in complex with its substrates and inhibitors;identification of interacting proteins by proteomics approach and potential in vivo electron-donors;and protein expression profiling of QR2 knockdown cell lines. The comprehensive approach will shed light on the unique catalytic properties and biological functions of QR2 and the understanding of QR2 polymorphism in relationship with certain neurological diseases, as QR2 polymorphism has been associated with idiopathic Parkinson's disease, schizophrenia, alcohol withdrawal symptoms and clozapine-induced aranulocytosis.